Historically, Pneumocystis pneumonia (PCP) and other opportunistic pneumonias have been major causes of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. The long-term objective of this study is to create an international, multi-center, longitudinal cohort that reflects the HIV/AIDS epidemic in Africa (Uganda), Europe (United Kingdom), and North America (United States) to study PCP and opportunistic pneumonias. We propose a prospective, longitudinal cohort study that will enroll and follow 600-750 HIV-infected patients per year who are admitted with pneumonia to Mulago Hospital (Kampala, Uganda);University College London Hospitals (London, UK);and San Francisco General Hospital (San Francisco, CA, US). Patients will be followed throughout their hospitalization and every 6 months after hospital discharge to determine the frequency and mortality of PCP and HIV-associated opportunistic pneumonias. We will also collect serum, oropharyngeal wash, Scope mouthwash, sputum, and bronchoscopy specimens to address hypothesis-driven research questions. We propose the following aims: Aim 1: To determine the frequency and mortality of HIV-associated opportunistic pneumonias in an international, multi-center, longitudinal cohort and to test the hypothesis that PCP is associated with increased mortality. Aim 2: To estimate the sensitivity and specificity of molecular tools for PCP and tuberculosis (TB) diagnosis and to test the hypotheses that 60-second oropharyngeal washing (OPW, gargle) specimens combined with polymerase chain reaction (PCR) assays are sensitive tests to diagnose PCP and TB. Aim 3: To test the hypothesis that Pneumocystis dihydropteroate synthase (DHPS) gene mutations are associated with an increased mortality and to explore potential mechanisms. Aim 4: To characterize the predominant Pneumocystis Msg-C variant recognized by subjects at each site, to examine systemic (serum) and local (BAL) antibody responses, and to test the hypothesis that the level of antibodies to the predominant variant is correlated with PCP status. In the future, we plan to expand the scientific focus to include other pneumonias, such as TB and bacterial pneumonia that are beyond the scope of this proposal, Relevance to public health: Pneumocystis pneumonia (PCP) is a significant cause of illness and death among human immunodeficiency virus (HIV)-infected and other immunocompromised persons. This study will examine newer methods to diagnose PCP and will determine whether Pneumocystis is becoming resistant to medications that are used to treat PCP. The development of rapid, non-invasive methods to diagnose PCP would be a significant advance, while the demonstration of drug resistance would have serious implications, given the limited PCP treatment medications currently available.